Antidepressants: A Triumph of Marketing Over Science?

David O. AntonuccioVeterans Affairs Sierra
Nevada Health Care System and University of Nevada School of Medicine

David D. BurnsStanford University

William G. DantonVeterans Affairs Sierra
Nevada Health Care System and University of Nevada School of Medicine

ABSTRACTIn a
meta-analysis of the Food and Drug Administration (FDA) database of
controlled trials used in the initial approval for the most popular
antidepressants, I.
Kirsch, T. J. Moore, A. Scoboria, and S. S. Nicholls (2002) found
that antidepressants demonstrated a clinically negligible advantage over
inert placebo. These results are surprising, because they come from
studies underwritten by the drug manufacturers. This analysis probably
overestimates the antidepressant effect because placebo washout
strategies, penetration of the blind, reliance on clinician ratings, use
of sedative medication, and replacement of nonresponders may penalize
the placebo condition or boost the drug condition. These findings do not
appear to justify the popularity of antidepressants, which may have been
fueled in part by publication bias and outstanding marketing.
Psychotherapy may offer an effective alternative with fewer medical
risks.

David O. Antonuccio, Veterans Affairs Sierra Nevada Health
Care System, Reno, Nevada, and Department of Psychiatry and Behavioral
Sciences, University of Nevada School of Medicine; David D. Burns,
Department of Psychiatry, Stanford University School of Medicine; William
G. Danton, Veterans Affairs Sierra Nevada Health Care System, Reno,
Nevada, and Department of Psychiatry and Behavioral Sciences, University
of Nevada School of Medicine.

Correspondence concerning this article should be addressed to David O.
Antonuccio, University of Nevada School of Medicine, 401 West 2nd Street,
Suite 216, Reno, Nevada 89503.E-mail: oliver2@aol.com

Apparently antidepressants work, but just barely better than inert
placebos. Kirsch,
Moore, Scoboria, and Nicholls (2002) have gone straight to the heart
of the Food and Drug Administration (FDA) database of blinded, randomized,
placebo-controlled trials used in the initial approval of the most popular
antidepressant medications, including fluoxetine, paroxetine, sertraline,
venlafaxine, nefazadone, and citalopram. The results of their analysis are
stunning and offer the potential for a paradigm shift in the way we view
the efficacy of antidepressant medications. They analyzed 38 studies
involving 6,944 patients treated for an average of 6 weeks and found that
approximately 80% of the antidepressant response was duplicated by
placebo. In the subsample of fluoxetine trials, the placebo response
duplicated 89% of the fluoxetine response.

Kirsch
et al. (2002) noted that at least six studies allowed replacement of
nonresponders. This may also inflate estimates of the drug response if it
is subtly related to side effects and limited primarily to the subjects in
the active drug condition (Moncrieff,
2001). A separate analysis excluding these studies might be
illuminating. Also, most studies allowed the prescription of a sedative,
consistent with findings from another recent meta-analysis of
antidepressant trials (Walsh,
Seidman, Sysko, & Gould, 2002). If patients in the drug condition
were more likely to take sedatives or antidepressants with sedative
properties, results could be distorted because there are at least 6 points
on the HAM-D that favor medications with sedative properties (Moncrieff,
2001).

Kirsch
et al. (2002) noted that the overall active drug effects from the
paroxetine, sertraline, and citalopram trials may have been inflated
because means were not reported from several studies that found
nonsignificant differences. In these trials with incomplete means, the
placebo response duplicated less of the antidepressant response than in
studies with complete data (72% vs. 82%), suggesting the presence of bias
due to selective reporting. Perhaps the FDA could ask the pharmaceutical
companies to resubmit the original data in order to have the most complete
and accurate database possible.

Klein
(2000) and Quitkin
(1999) have argued that because antidepressants have been established
as effective in the treatment of depression, trials that do not find a
statistical advantage of antidepressants over placebo lack "assay
sensitivity" (i.e., the ability to detect specific treatment effects). In
other words, they argue that something is wrong with the sampling or
methodology of such trials, and the results should be discounted or
discarded. If that logic were applied to this meta-analysis, more than
half of the studies would have to be discarded, a strategy that would
seriously distort the overall results. This example graphically
illustrates the hazards of using established "fact" as a reason to throw
out newer contradictory data (see Otto
& Nierenberg, in press).

In Search of "True" Antidepressant Effects

Kirsch
et al. (2002) have proposed the balanced placebo design as a way to
untangle the "true" influence of the drug and placebo. This 2 × 2
factorial design manipulates what drug patients are told they are taking
(antidepressant or placebo) with what drug they are actually taking
(antidepressant or placebo). As an example, this design proved useful in a
smoking cessation study where it was shown that the actual drug condition
had less impact on withdrawal symptoms and relapse than the believed drug
condition (Gottlieb,
Killen, Marlatt, & Taylor, 1987).

Consumer Reports has documented marketing strategies (Miracle
or Media Drugs, 1992; Pushing
Drugs to Doctors, 1992) that include but are not limited to the
following: (a) giving free samples and information to doctors, (b)
advertising in medical journals, (c) using "ask your doctor" media
advertisements aimed directly at the consumer (see Wolfe,
2002), (d) sponsoring promotional dinner meetings with substantial
gifts or even cash provided for attendees, (e) paying consultants to speak
at scientific meetings where it is possible to circumvent FDA guidelines
that require disclosure of side effects, (f) funding only those research
projects that have a high likelihood of producing favorable results for a
particular drug company's product (see Bodenheimer,
2000), (g) terminating negative studies before they are ready for
publication, (h) involving large numbers of physicians in studies not
intended to yield publishable information but simply designed to yield
maximum product exposure, (i) including "look alike" publication
supplements in professional journals, (j) offering to pay journalists to
cover their products, (k) offering prepackaged information for journalists
in the form of video news releases that give the appearance of having been
independently developed, and (l) helping to fund patient advocacy and
other public interest groups so the consumer group appears to be publicly
carrying the banner of a particular drug.

A Bitter Pill to Swallow

Kirsch
et al. (2002) have convincingly demonstrated, using pharmaceutical
industry data, that the image of antidepressants as powerfully more
effective than placebo is not supported by the data. The small advantage
over inert placebo credited to antidepressants is quite possibly a
methodological artifact (Moncrieff,
2002). It could be argued that the patients randomly assigned to
placebo are the lucky ones, because they derive a benefit virtually
comparable with the medication condition without the associated medical
risks.